Description

It is intended for the induction of general anesthesia by intravenous
injection.

The drug etomidate is chemically identified as
(R)-(+)-ethyl-1-(1-phenylethyl)-1H-imidazole -5-carboxylate and has the
following structural formula:

CLINICAL PHARMACOLOGY

Etomidate is a hypnotic drug without analgesic activity.
Intravenous injection of etomidate produces hypnosis characterized by a rapid
onset of action, usually within one minute. Duration of hypnosis is dose
dependent but relatively brief, usually three to five minutes when an average
dose of 0.3 mg/kg is employed. Immediate recovery from anesthesia (as assessed
by awakening time, time needed to follow simple commands and time to perform
simple tests after anesthesia as well as they were performed before anesthesia),
based upon data derived from short operative procedures where intravenous
etomidate was used for both induction and maintenance of anesthesia, is about as
rapid as, or slightly faster than, immediate recovery after similar use of
thiopental. These same data revealed that the immediate recovery period will
usually be shortened in adult patients by the intravenous administration of
approximately 0.1 mg of intravenous fentanyl, one or two minutes before
induction of anesthesia, probably because less etomidate is generally required
under these circumstances (consult the package insert for fentanyl before
using).

The most characteristic effect of intravenous etomidate on the respiratory
system is a slight elevation in arterial carbon dioxide tension (PaCO2). See also ADVERSE
REACTIONS.

Reduced cortisol plasma levels have been reported with induction doses of 0.3
mg/kg etomidate. These persist for approximately 6 to 8 hours and appear to be
unresponsive to ACTH administration.

The intravenous administration of up to 0.6 mg/kg of etomidate to patients
with severe cardiovascular disease has little or no effect on myocardial
metabolism, cardiac output, peripheral circulation or pulmonary circulation. The
hemodynamic effects of etomidate have in most cases been qualitatively similar
to those of thiopental sodium, except that the heart rate tended to increase by
a moderate amount following administration of thiopental under conditions where
there was little or no change in heart rate following administration of
etomidate. However, clinical data indicates that etomidate administration in
geriatric patients, particularly those with hypertension, may result in
decreases in heart rate, cardiac index, and mean arterial blood pressure. There
are insufficient data concerning use of etomidate in patients with recent severe
trauma or hypovolemia to predict cardiovascular response under such
circumstances.

Limited clinical experience, as well as animal studies, suggests that
inadvertent intra-arterial injection of etomidate, unlike thiobarbiturates, will
not usually be followed by necrosis of tissue distal to the injection site.
Intra-arterial injection of etomidate is, however, not recommended.

Etomidate induction is associated with a transient 20-30% decrease in
cerebral blood flow. This reduction in blood flow appears to be uniform in the
absence of intracranial space occupying lesions. As with other intravenous
induction agents, reduction in cerebral oxygen utilization is roughly
proportional to the reduction in cerebral blood flow. In patients with and
without intracranial space occupying lesions, etomidate induction is usually
followed by a moderate lowering of intracranial pressure, lasting several
minutes. All of these studies provided for avoidance of hypercapnia. Information
concerning regional cerebral perfusion in patients with intracranial space
occupying lesions is too limited to permit definitive conclusions.

Etomidate is rapidly metabolized in the liver. Minimal hypnotic plasma levels
of unchanged drug are equal to or higher than 0.23 μg/mL; they decrease rapidly
up to 30 minutes following injection and thereafter more slowly with a half-life
value of about 75 minutes. Approximately 75% of the administered dose is
excreted in the urine during the first day after injection. The chief metabolite
is R-(+)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid, resulting from
hydrolysis of etomidate, and accounts for about 80% of the urinary excretion.
Limited pharmacokinetic data in patients with cirrhosis and esophageal varices
suggest that the volume of distribution and elimination half-life of etomidate
are approximately double that seen in healthy subjects.

In clinical studies, elderly patients demonstrated decreased initial
distribution volumes and total clearance of etomidate. Protein binding of
etomidate to serum albumin was also significantly decreased in these
individuals.

Reduced plasma cortisol and aldosterone levels have been reported following
induction doses of etomidate. These results persist for approximately 6-8 hours
and appear to be unresponsive to ACTH stimulation. This probably represents
blockage of 11 beta-hydroxylation within the adrenal cortex.

INDICATIONS AND USAGE

Etomidate is a hypnotic drug without analgesic activity.
Intravenous injection of etomidate produces hypnosis characterized by a rapid
onset of action, usually within one minute. Duration of hypnosis is dose
dependent but relatively brief, usually three to five minutes when an average
dose of 0.3 mg/kg is employed. Immediate recovery from anesthesia (as assessed
by awakening time, time needed to follow simple commands and time to perform
simple tests after anesthesia as well as they were performed before anesthesia),
based upon data derived from short operative procedures where intravenous
etomidate was used for both induction and maintenance of anesthesia, is about as
rapid as, or slightly faster than, immediate recovery after similar use of
thiopental. These same data revealed that the immediate recovery period will
usually be shortened in adult patients by the intravenous administration of
approximately 0.1 mg of intravenous fentanyl, one or two minutes before
induction of anesthesia, probably because less etomidate is generally required
under these circumstances (consult the package insert for fentanyl before
using).

The most characteristic effect of intravenous etomidate on the respiratory
system is a slight elevation in arterial carbon dioxide tension (PaCO2). See also ADVERSE
REACTIONS.

Reduced cortisol plasma levels have been reported with induction doses of 0.3
mg/kg etomidate. These persist for approximately 6 to 8 hours and appear to be
unresponsive to ACTH administration.

The intravenous administration of up to 0.6 mg/kg of etomidate to patients
with severe cardiovascular disease has little or no effect on myocardial
metabolism, cardiac output, peripheral circulation or pulmonary circulation. The
hemodynamic effects of etomidate have in most cases been qualitatively similar
to those of thiopental sodium, except that the heart rate tended to increase by
a moderate amount following administration of thiopental under conditions where
there was little or no change in heart rate following administration of
etomidate. However, clinical data indicates that etomidate administration in
geriatric patients, particularly those with hypertension, may result in
decreases in heart rate, cardiac index, and mean arterial blood pressure. There
are insufficient data concerning use of etomidate in patients with recent severe
trauma or hypovolemia to predict cardiovascular response under such
circumstances.

Limited clinical experience, as well as animal studies, suggests that
inadvertent intra-arterial injection of etomidate, unlike thiobarbiturates, will
not usually be followed by necrosis of tissue distal to the injection site.
Intra-arterial injection of etomidate is, however, not recommended.

Etomidate induction is associated with a transient 20-30% decrease in
cerebral blood flow. This reduction in blood flow appears to be uniform in the
absence of intracranial space occupying lesions. As with other intravenous
induction agents, reduction in cerebral oxygen utilization is roughly
proportional to the reduction in cerebral blood flow. In patients with and
without intracranial space occupying lesions, etomidate induction is usually
followed by a moderate lowering of intracranial pressure, lasting several
minutes. All of these studies provided for avoidance of hypercapnia. Information
concerning regional cerebral perfusion in patients with intracranial space
occupying lesions is too limited to permit definitive conclusions.

Etomidate is rapidly metabolized in the liver. Minimal hypnotic plasma levels
of unchanged drug are equal to or higher than 0.23 μg/mL; they decrease rapidly
up to 30 minutes following injection and thereafter more slowly with a half-life
value of about 75 minutes. Approximately 75% of the administered dose is
excreted in the urine during the first day after injection. The chief metabolite
is R-(+)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid, resulting from
hydrolysis of etomidate, and accounts for about 80% of the urinary excretion.
Limited pharmacokinetic data in patients with cirrhosis and esophageal varices
suggest that the volume of distribution and elimination half-life of etomidate
are approximately double that seen in healthy subjects.

In clinical studies, elderly patients demonstrated decreased initial
distribution volumes and total clearance of etomidate. Protein binding of
etomidate to serum albumin was also significantly decreased in these
individuals.

Reduced plasma cortisol and aldosterone levels have been reported following
induction doses of etomidate. These results persist for approximately 6-8 hours
and appear to be unresponsive to ACTH stimulation. This probably represents
blockage of 11 beta-hydroxylation within the adrenal cortex.

CONTRAINDICATIONS

Etomidate is contraindicated in patients who have shown hypersensitivity to it.

WARNINGS

INTRAVENOUS ETOMIDATE SHOULD BE ADMINISTERED ONLY BY PERSONS
TRAINED IN THE ADMINISTRATION OF GENERAL ANESTHETICS AND IN THE MANAGEMENT OF
COMPLICATIONS ENCOUNTERED DURING THE CONDUCT OF GENERAL ANESTHESIA.

BECAUSE OF THE HAZARDS OF PROLONGED SUPPRESSION OF ENDOGENOUS CORTISOL AND
ALDOSTERONE PRODUCTION, THIS FORMULATION IS NOT INTENDED FOR ADMINISTRATION BY
PROLONGED INFUSION.

PRECAUTIONS

Do not administer unless solution is clear and container is
undamaged. Discard unused portion (see DOSAGE AND
ADMINISTRATION).

1. Carcinogenesis, Mutagenesis, Impairment of
Fertility:

No carcinogenesis or mutagenesis studies have been carried out on
etomidate. The results of reproduction studies showed no impairment of fertility
in male and female rats when etomidate was given prior to pregnancy at 0.31,
1.25 and 5 mg/kg (approximately 1X, 4X and 16X human dosage).

2. Pregnancy Category C.

Etomidate has been shown to have an embryocidal effect in rats
when given in doses 1 and 4 times the human dose. There are no adequate and
well-controlled studies in pregnant women. Etomidate should be used during
pregnancy only if the potential benefit justifies the potential risks to the
fetus. Etomidate has not been shown to be teratogenic in animals. Reproduction
studies with etomidate have been shown to:

There are insufficient data to support use of intravenous
etomidate in obstetrics, including Caesarean section deliveries. Therefore, such
use is not recommended.

4. Nursing Mothers:

It is not known whether this drug is excreted in human milk.
Because many drugs are excreted in human milk, caution should be exercised when
etomidate is administered to a nursing mother.

5. Pediatric Use:

There are inadequate data to make dosage recommendations for
induction of anesthesia in patients below the age of ten (10) years; therefore,
such use is not recommended (see also DOSAGE AND
ADMINISTRATION).

Elderly patients may require lower doses of etomidate than younger patients.
Age-related differences in phamacokinetic parameters have been observed in
clinical studies (see CLINICAL
PHARMACOLOGY and DOSAGE AND
ADMINISTRATION).

This drug is known to be substantially excreted by the kidney, and the risk
of toxic reactions to this drug may be greater in patients with impaired renal
function. Because elderly patients are more likely to have decreased renal
function, care should be taken in dose selection and it may be useful to monitor
renal function.

7. Plasma Cortisol Levels:
Induction doses of etomidate have been associated with reduction
in plasma cortisol and aldosterone concentrations (see CLINICAL PHARMACOLOGY). These have
not been associated with changes in vital signs or evidence of increased
mortality; however, where concern exists for patients undergoing severe stress,
exogenous replacement should be considered.

ADVERSE REACTIONS

The most frequent adverse reactions associated with use of
intravenous etomidate are transient venous pain on injection and transient
skeletal muscle movements, including myoclonus:

Transient venous pain was observed immediately following
intravenous injection of etomidate in about 20% of the patients, with
considerable difference in the reported incidence (1.2% to 42%). This pain is
usually described as mild to moderate in severity but it is occasionally judged
disturbing. The observation of venous pain is not associated with a more than
usual incidence of thrombosis or thrombophlebitis at the injection site. Pain
also appears to be less frequently noted when larger, more proximal arm veins
are employed and it appears to be more frequently noted when smaller, more
distal, hand or wrist veins are employed.

Transient skeletal muscle movements were noted following use of
intravenous etomidate in about 32% of the patients, with considerable difference
in the reported incidence (22.7% to 63%). Most of these observations were judged
mild to moderate in severity but some were judged disturbing. The incidence of
disturbing movements was less when 0.1 mg of fentanyl was given immediately
before induction. These movements have been classified as myoclonic in the
majority of cases (74%), but averting movements (7%), tonic movements (10%), and
eye movements (9%) have also been reported. No exact classification is
available, but these movements may also be placed into three groups by
location:

a. Most movements are bilateral. The arms, legs, shoulders, neck, chest wall,
trunk and all four extremities have been described in some cases, with one or
more of these muscle groups predominating in each individual case. Results of
electroencephalographic studies suggest that these muscle movements are a
manifestation of disinhibition of cortical activity; cortical
electroencephalograms, taken during periods when these muscle movements were
observed, have failed to reveal seizure activity.

b. Other movements are described as either unilateral or having a
predominance of activity of one side over the other. These movements sometimes
resemble a localized response to some stimuli, such as venous pain on injection,
in the lightly anesthetized patient (averting movements). Any muscle group or
groups may be involved, but a predominance of movement of the arm in which the
intravenous infusion is started is frequently noted.

c. Still other movements probably represent a mixture of the first two
types.

Skeletal muscle movements appear to be more frequent in patients who also
manifest venous pain on injection.

OTHER ADVERSE OBSERVATIONS

Respiratory System:
Hyperventilation, hypoventilation, apnea of short duration (5 to 90 seconds with
spontaneous recovery); laryngospasm, hiccup and snoring suggestive of partial
upper airway obstruction have been observed in some patients. These conditions
were managed by conventional countermeasures.

Circulatory System:
Hypertension, hypotension, tachycardia, bradycardia and other arrhythmias have
occasionally been observed during induction and maintenance of anesthesia. One
case of severe hypotension and tachycardia, judged to be anaphylactoid in
character, has been reported.

Geriatric patients, particularly those with hypertension, may be at increased
risk for the development of cardiac depression following etomidate
administration (see CLINICAL
PHARMACOLOGY).

Gastrointestinal System:
Postoperative nausea and/or vomiting following induction of anesthesia with
etomidate is probably no more frequent than the general incidence. When
etomidate was used for both induction and maintenance of anesthesia in short
procedures such as dilation and curettage, or when insufficient analgesia was
provided, the incidence of postoperative nausea and/or vomiting was higher than
that noted in control patients who received thiopental.

OVERDOSAGE

Overdosage may occur from too rapid or repeated injections. Too
rapid injection may be followed by a fall in blood pressure. No adverse
cardiovascular or respiratory effects attributable to etomidate overdose have
been reported.

In the event of suspected or apparent overdosage, the drug should be
discontinued, a patent airway established (intubate, if necessary) or maintained
and oxygen administered with assisted ventilation, if necessary.

The LD50 of etomidate administered intravenously to
rats is 20.4 mg/kg.

DOSAGE AND ADMINISTRATION

Etomidate injection is intended for administration only by the
intravenous route (see CLINICAL
PHARMACOLOGY). The dose for induction of anesthesia
in adult patients and in pediatric patients above the age of ten (10) years will
vary between 0.2 and 0.6 mg/kg of body weight, and it must be individualized in
each case. The usual dose for induction in these patients is 0.3 mg/kg, injected
over a period of 30 to 60 seconds. There are inadequate data to make dosage
recommendations for induction of anesthesia in patients below the age of ten
(10) years; therefore, such use is not recommended. Geriatric patients may
require reduced doses of etomidate.

Smaller increments of intravenous etomidate may be administered to adult
patients during short operative procedures to supplement subpotent anesthetic
agents, such as nitrous oxide. The dosage employed under these circumstances,
although usually smaller than the original induction dose, must be
individualized. There are insufficient data to support this use of etomidate for
longer adult procedures or for any procedures in pediatric patients; therefore,
such use is not recommended. The use of intravenous fentanyl and other
neuroactive drugs employed during the conduct of anesthesia may alter the
etomidate dosage requirements. Consult the prescribing information for all other
such drugs before using.

Premedication: Etomidate
injection is compatible with commonly administered pre-anesthetic medications,
which may be employed as indicated. See also CLINICAL
PHARMACOLOGY, ADVERSE
REACTIONS, and dosage recommendations for
maintenance of anesthesia.

Etomidate hypnosis does not significantly alter the usual dosage requirements
of neuromuscular blocking agents employed for endotracheal intubation or other
purposes shortly after induction of anesthesia.

Parenteral drug products should be inspected visually for particulate matter
and discoloration prior to administration, whenever solution and container
permit.

To prevent needle-stick injuries, needles should not be recapped, purposely
bent, or broken by hand.

HOW SUPPLIED

HOW SUPPLIED

Amidate™ (etomidate injection) is supplied in single-dose
containers as follows: